The hypothalamo-pituitary-adrenocortical (HPA) axis is responsible for stress-induced glucocorticoid secretion into the systemic circulation. Glucocorticoids have multiple beneficial effects for coping with rapid changes in the environment; however, mismanagement of glucocorticoid secretion has multiple deleterious effects on the organism, and has been implicated in pathology associated with major depression, chronic stress and age-related cognitive decline. The goal of this proposal is to examine the manner in which the brain integrates the HPA stress response, focusing on the primary neurosecretory neurons in the hypothalamic paraventricular nucleus (corticotropin-releasing hormone (CRH) neurons) and their relationship to vital control elements located in limbic system sites. Initial studies (Specific Aim 1) will characterize the time course of stress-induced changes in the physiology of CRH neurons at the level of adrenocorticotrophic hormone secretagogue gene transcription, biosynthesis and secretion, and the sensitivity these changes to glucocorticoid feedback. This information will then be used to assess the influence of limbic structures (the hippocampus, amygdala and lateral septum) on stress- regulatory processes via lesion analysis (Specific Aim 2). Studies will determine whether limbic structures, which have been implicated in glucocorticoid-related HPA dysfunction, indeed exert actions on the stress response at the level of the CRH neuron. The interaction between glucocorticoid feedback and limbic actions will be investigated to determine whether effects at the CRH neuron can be associated with changes in negative feedback, or alternatively to limbic modulation of stress sensitivity. Finally, anatomical studies will define how limbic influences are conveyed to the CRH neuron, and define candidate neurochemical systems involved in HPA regulation. In combination, these experiments should provide a """"""""blueprint"""""""" of circuits regulating CRH neuronal stress responses, and identify focal points for study of the interrelationships between HPA regulation, stress and human disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH049698-04
Application #
2249085
Study Section
Behavioral Neuroscience Review Committee (BNR)
Project Start
1992-09-15
Project End
1997-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Myers, Brent; Carvalho-Netto, Eduardo; Wick-Carlson, Dayna et al. (2016) GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity. Neuropsychopharmacology 41:1530-9
de Kloet, Annette D; Krause, Eric G; Solomon, Matia B et al. (2015) Adipocyte glucocorticoid receptors mediate fat-to-brain signaling. Psychoneuroendocrinology 56:110-9
Solomon, Matia B; Loftspring, Matthew; de Kloet, Annette D et al. (2015) Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice. Endocrinology 156:2843-53
McKlveen, J M; Myers, B; Herman, J P (2015) The medial prefrontal cortex: coordinator of autonomic, neuroendocrine and behavioural responses to stress. J Neuroendocrinol 27:446-56
Solomon, Matia B; Wulsin, Aynara C; Rice, Taylor et al. (2014) The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test. Horm Behav 65:363-71
Myers, Brent; Mark Dolgas, C; Kasckow, John et al. (2014) Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct 219:1287-303
Uchoa, E T; Aguilera, G; Herman, J P et al. (2014) Novel aspects of glucocorticoid actions. J Neuroendocrinol 26:557-72
Myers, Brent; McKlveen, Jessica M; Herman, James P (2014) Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 35:180-196
Flak, Jonathan N; Myers, Brent; Solomon, Matia B et al. (2014) Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress. Eur J Neurosci 39:1903-11
Ghosal, Sriparna; Myers, Brent; Herman, James P (2013) Role of central glucagon-like peptide-1 in stress regulation. Physiol Behav 122:201-7

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